(a) Field of the Invention
The present invention relates to novel compounds which are inhibitors of Protein ARginine Methyl Transferases (PRMTs), to methods of using such compounds for inhibiting protein methyltransferases, to methods of using such compounds in the treatment of hyperproliferative, inflammatory, infectious, and immunoregulatory disorders and diseases, and to pharmaceutical compositions containing such compounds.
The compounds and pharmaceutical compositions of the invention are particularly well suited as inhibitors of protein methyltransferases and, consequently, can be advantageously used as therapeutic agents for the treatment of certain diseases and/or conditions, including cancer, asthma, COPD, allergic diseases; rheumatoid arthritis, spinal muscular atrophy, atherosclerosis, and psoriasis; viral infections; solid organ transplant rejection, osteoarthritis, and inflammatory bowel syndrome. This invention also relates to methods of using the compounds of this invention alone or in combination with other pharmaceutically active agents.
(b) Summary of the Related Art
PRMTs are enzymes that catalyze the transfer of methyl groups from S-Adenosyl-L-Methionine (SAM) to specific arginine residues of proteins. Arginine methylation of proteins has been implicated to play roles in pre-mRNA splicing, nucleo-cytoplasmic RNA transport, signal transduction and transcriptional activation.
To date, eight family members have been identified (PRMTs 1-8) in mammalian cells and each appear to have distinct substrate preferences and biological functions. Co-activator Associated Arginine Methyltransferase-1 (CARM-1; also called PRMT4) has been shown to methylate histone H3 both in vitro and in vivo, and it is speculated that this modification positively affects chromatin remodeling and thus transcriptional activation. CARM-1 also methylates non-histone proteins, such as CREB-binding protein (CBP)/p300 (Chevillard-Briet et al., 2002; Lee et al., 2005; Xu et al., 2001), steroid receptor co-activator (SRC)-3 (Naeem et al., 2006), poly-A binding protein (PABP) (Lee and Bedford, 2002), members of the Hu family of proteins HuD and HuR (Li et al., 2002), and splicing factors CA150, SAP49, SmB, and U1C (Espego et al., 2002; Cheng et al., 2007).
CARM-1 has oncogenic potential, through its ability to modulate chromatin organization, regulate transcription and increase the half-life of specific mRNAs involved in cancer. CARM-1 plays a co-activator role in androgen- and estrogen-induced gene expression mediated by the nuclear hormone receptor family of transcription factors (Chen et al., 1999). Mutations of critical residues in the catalytic domain compromise the co-activator function of CARM-1 and the arginine-specific histone methylation of the promoter regions of nuclear receptor-responsive genes, suggesting that the integrity of its methyltransferase domain is indispensable for its co-activator function (Chen et al., 1999; Koh et al., 2001; Wang et al., 2001). CARM-1 is also involved in the activation of cyclin E1 gene expression (El Messaoudi et al., 2006). CARM-1 levels are significantly higher in prostatic intraepithelial neoplasia and prostatic adenocarcinoma compared to benign prostate tissue, and higher in patients with androgen-independent prostatic adenocarcinoma compared to patients without previous hormonal treatment. From these findings, it is an attractive chemotherapeutic option to inhibit the enzymatic function of CARM-1 using a small molecule inhibitor.
CARM-1 may also play a role in inflammation and viral gene expression. Studies of cells derived from CARM-1-null mice and knockdown experiments reveal that CARM-1 acts as a co-activator for NF-kappaB in the regulation of inflammatory gene expression (Covic et al., 2004; Teferedegne et al., 2006), and cooperates with CBP and CIITA in the expression of the major histocompatibility class II gene in response to interferon-gamma. CARM-1 is also implicated in the transactivation of the human T-cell lymphotropic virus type 1 long terminal repeat through direct interaction with Tax (Jeong et al., 2006). These findings suggest that inhibition of CARM-1 may also be effective against viral infection and inflammatory disorders.
It would be highly desirable to be provided with novel compounds which are inhibitors of protein arginine methyl transferase. It would also be highly desirable to be provided with novel compounds which are inhibitors of CARM-1.